Production of amidines



bon radical).

Patented May 8, 1945 monucrron on AMIDINES Harry James Barber, Gidea Park, Romi'ord, and Alan David Henderson Self, Hornchurch, England, assignors to May & Baker Limited, Degenham, England, a British company No Drawing. Application August 19, 1942, Serial N0. 455,336. In Great Britain August 19, 1941 6 Claims.

This invention relates to the production of amidines and has for its'obiect to provide a new and improved process forthe production of these compounds.

Hitherto, amidines have been prepared, for example, by treating the corresponding cyano compounds with anhydrous alcoholic hydrogen chloride or hydrogen bromide and reacting the imino ether hydrohalide thus formed with ammonia or salts thereof. An alternative method consists in reacting the correspondin nitrile with an alkali metal amide and hydrolysing the product to form the corresponding amidine or hydrohalide thereof.

It has now been found that amidines can be prepared from the corresponding amidoximes. The present invention, therefore, consists in a process for the production of amidines which,

comprises the reduction of amidoximes, includmg amidoximes substituted in the amino group (e. g., amidoximes substituted by a hydrocar- The amidoximes employed as starting material are made in manner known per se, for example they may be prepared by the action of hydrcxylamine upon the corresponding nitrile.

The reduction of the amidoxime may be car-l made the catholyte of a separated diaphragm gen in the presence of a catalyst of the group 1 known to be capable of catalysing the reduction of an organic nitrogen group such as an N02 group or an =NOH group to the corresponding NH: group. A catalyst of the nickel group is preferred, Raney nickel being particularly useful. However, satisfactory results are also obtained 18y employing, for example, electrolytic reducion.

According to one embodiment of the present invention, the amidoxime is dissolved in a suitable solvent and hydrogenatedat a convenient pressure, for example atmospheres, and at elevated temperature, for exampiefbetween 60 and 80 C. in the presence of a quantity of Raney nickel catalyst. It is usually convenient in order to obtain a soluble reduction product, to add to the solution an acid, or the ammonium salt of such acid, the amidine salt of which is relatively soluble. Examples of suitable acids are hydrochloric acid and lactic acid; suitable ammonium salts are ammonium chloride and ammonium electrolytic cell, which may comprise a carbon anode and a coated lead cathode. After electrolysis of the catholyte solution, the required amldine is removed therefrom, conveniently in the form of a salt, for example, the hydrochloride or picrate;

The process of the present invention can be applied to the production of amidines of the general formula R.C(=NH) NHR1 where Ris a monovalent radical (including hydrogen) and R1 represents hydrogen or a substituent radical. Ex-

' which the amino group is replaced by a nitrogen atom forming part of a closed ring, e. g., a piperidine ring. The corresponding amidoximes possess the general formula NOH 'where'A'represents a nitrogen atom forming part of a closed ring. The process is also applicable to the production of di-amidines and an important embodiment of the. presentin'vention consists in the production, ,by the process hereinbefore defined, of di-amidines of the general formula:

, NI-h(NH=)CB+x--B-C(=NH)NIh wherein B represents an aromatic nucleus (pref- I addition of excess alcoholic picric acid.

(CH2) a-Wh81'6 n is a whole number from 1 to 12, in which group one or more the methylene groups may be replaced by an atomof oxygen or of sulphur or by an --N H-group, or an ethylenic linkage -CR=CR1- where R and R1 are the same or different and represent hydrogen atoms or hydrocarbon groups (preferably lower alkyl groups). The corresponding amidoximes possess in general the formula wherein B and K have the significance above In the preparation of amidines which are unsubstituted in the amidine group it is also possible to employ N-hydroxy amidoximes, i. e., -C(=NOH)NHOH since on reduction both hydroxy groups are replaced by hydrogen atoms. In this embodiment it is preferred to carry out the reacticnin the presence of an acid. I I

The present invention is illustrated by the fol-= lowing examples:

Example I Emmple II e. of benzamidoxime prepared by known methods from benzo nitrile, were dissolved in 120 c. c. s. oi dry ethyl alcohol and hydrogenated at atmospheres pressure and at 78 C. .in the access. 1-

mus. The solution so obtained was hydrogenated at 30 atmospheres pressure, and at C. in the presence or 1 gm. Raney nickel catalyst. The reaction mixture was filtered hot and the filtrate was'treated with vol. of conc. hydrochloric acid. This precipitated 4:4'-diamidino-diphenoxy propane dihydrochloride.

The product was then cooled and filtered,

washed with alcohol and acetone and finally dried at 50 C. tor a short time.

Example V 5.85 gm. of s:E-diphenoxypentane-4,4-diamidoxime dihydrochloride (prepared by known methods from ,d'-x:'licyano ate diphenoxypentane) were dissolved in c. c. s. of ethyl alcohol by warming. Suflicient ammonia was added to presence of 1 gm. of Honey nickel catalyst. On

completion of the reduction, the product was 111- tered and the filtrate evaporated to dryness. The residue was. dissolved in a small amount of ethyl 4 alcohol and evaporated. The crystalline product; dissolved readily in water; from the aqueous solution benzamidine picrate was obtained by addition of excess of aqueous picric acid solution. Y

Example III 15 gms. of phenyl acetamidoxime, prepared by known methods,'were suspended in 120 c. c. of water and treated with 9.5 c. c. of cone. hydro-' "chloric acid till complete solution was. effected.

Concentrated ammonia (7.0 c. c.) was then added till the sdlution became just alkaline to litmus. The product Was hydrogenated at 30 atmospheres pressure, and at 60 C. in presence of 1 gm. Raney nickel catalyst. Hydrogenation'was complete in' mins. The faintly acid'solution was evab'orated .to dryness under reduced pressure and the residue was taken up in hot alcohol.

- 'Phenyl acetamidine picrate was obtained g f l5 gins. oi diphenoxy propane di'amidoxime I (prepared by the action of a solution of hydroxyl-l with just sumcient. conc. hydrochloric acid (8.6 c. c.) to dissolve. I The solution of thehydrochloride so obtained was treated .with 8.6 c. c-01 am- 'monia (5 g. of 0.88 so s.) tilliust neutr l tolit- 75 l w'rnombc MR Q render the solution alkaline to litmus and then an alcoholic suspension of 1 gram catalyst was added.

Reduction was achieved by means-0t hydrogen at 30 atmospheres and 65 C. in the usual catalytic reduction apparatus. On completion of reduction, the catalyst was removed by filtration and the hydrochlorideof the amidine (i. e., 4,4- diamidine ale diphenoxypentane dihydrochloride) was then isolated by the addition or acetone.

Example VI 2.27 guns. of mnaphthamidoxime, prepared by known methods, were dissolved in c. c. of methyl alcohol and hydrogenated at 30 atmospheres pressure and 60 C. in presence of 0.25 gm. of Raney nickel catalyst. Hydrogenation was complete in '70 minutes. After hydrogenation. the catalyst was filtered oil, and the filtrate evaporated almost to dryness, at reduced pressure. The small amount otresidue was taken up in 2N.-HC1 until just permanently acid to Congo. The reaction mixture was then charcoaled and filtered. The filtrate was then treated with an excess of saturated aqueous picric acid solution. The precipitated plcrate was filtered off, and crystallised three times from aqueous alcohol. The picrate finally obtained had M. P. 194 C. (with decomp.) Mixed M. P. with the picrate obtained oi. Raney nickel "froman authentic specimen of anaphthamidine was ism-19a" o. (doc).

Example VII 100 c. c. or ethyl alcohol and hydrogenated at 30 atmospheres pressure and- 60 C. in the presence of 0.5 gm. of Raney nickel catalyst. Reduction was complete in one hour. The catalyst was illtered off and the solution concentrated to dryness. stirred-with water and filtered. Almost the theo- "rectical amount'of. N-phenylbenzamidlne' (M. P.

'1127 c.) was obtained.

Example VIII I 5.8 gms. of N(-diethylamino-n-amyl-6-)-bcnzamidoxime prepared by the reaction 0! bcnzhy.

droximicchloride and e-diethylamino-a-cmino pentane inether and having M. 19.79 C.) were aseaeii Example IX 7.6 gins. of N-oxybenzamidomme were dissolved in 150 c. c. of methanol with the addition of 4.5 ems. of lactic acid and the solution was hydrogenated at 30 atmosmpheres and 50 C. in the presence of 75 gms. of Fancy nickel catalyst. Reduction was complete in one hour and after coolme the catalyst was removed by filtration. The solvent was distilled on and the residue dissolved in 100 c. c. of water. A small amount of insolulole material was filtered 01? and hot saturated picric acid solution was added to 'the filtrate. Benzamidine picrate separated as a voluminous mass of yellow needles; after cooling it was filtered on and washed with water and then recrystallised from alcohol (M; P. 230 0.).

Example X 0.2 arms. of benzoyl piperidineoxime were dis- I solved in 100 c. 0. ethanol and hydrogenated at 30 atmospheres and 60 C. in the presence of 0.6 gm. oi Raney nickel catalyst. After completion of reduction the catalyst was filtered ed and the filtrate concentrated to small bulk. Treatment with picric acid gave the picrate of the hitherto unknown m-imino benzyl piperidine; it formed long yellow needles from alcohol M. P. 174 C.

Example X1 5 g. of benzamidoxime were dissolved in 40 c. c. s. of 3.3% HCl and-made the catholyte of a separated diaphragm electrolytic cell, consisting of a carbon anode and a. coated lead cathode. The

, cathode was previously prepared by anodic oxidation in 20% H2804 solution, using a current den- Example XI! minutes, using a current density of apprommately 0.05 amp. per sq. cm.. and keeping the temper= ature at approximately C.

From the catholyte solution after electrolysis, 4:4'-diamidino-a,y-diphencxy propane was conveniently isolated as its hydrochloride.

We claim:

1. Process of converting an amidoxime to a corresponding amidine by reducing the =N0'H group of such amidoxime to an imino group.

which comprises hydrogenating the amidoxime in the presence of a, metal hydrogenation oatalyst.

2. Process of converting an amidoxime to a corresponding amidine by reducing the :NOH group of an amidoxime to an imino group, which comprises hydrogenating the amidoxirne in the presence of a. metal hydrogenation catalyst at superatmospheric pressure and at elevated temperature.

3. Process of converting a member of the class consisting of an amidoxime and a diamidoxirne to a corresponding amidine by reducing =NOH of a said member to :NH, which comprises hydrogenating a said member in solution in the presence of Raney-nickel catalyst at superatmospheric pressure and at elevated temperature.

4. Process for the production of 4:'-diamidino-alpha-gamma-diphenoxy-propane, which comprises the hydrogenation of alpha-gammadiphenoxy-propane-z'-diamidoxime in solution in the presence of a nickel hydrogenation catalyst at a pressure of about atmospheres and at a temperature about C.

5. Process for the production of 4:4'-diamidino-alpha:epsilon-diphenoxy-pentane, w h i c h comprises the hydrogenation of alphazepsilondiphenoxy-pentane-4:4'-diamidoxime in solution in the presence of a nickel hydrogenation catalyst at a. pressure of about 30 atmospheres and at a temperature about C.

2 g. a,'y-dfphenoxy propane eze' -diamidoxime were dissolved in 30 c. c. s. of 0.66% E01 and made the catholyte of a separated diaphragm cell as described in Example m. The solution of the *anridoxime hydrochloride was electrolysed for 6. Process for the production of 4:4'-diamidino-diphenyl-ethylene, which comprises the hydrogenation of diphenyl-ethylene-4:4-diamidoxime in solution in the presence of a nickel hydrogenation catalyst at a pressure of about 30 atmospheres and at a temperature about 60 C.

HARRY JMES BARBER. ALAN DAVID HENDERSON SELF. 

